A topical vaginal combination microbicide will help contain the spread of the HIV and HSV pandemic by allowing women to protect themselves against HIV/HSV infection and possibly from other sexually transmitted diseases, especially when condoms are considered unacceptable or are unavailable. The microbicide must be nonirritating and not enhance infection. Several microbicides have failed clinical trials because of lack of efficacy, possibly from limited residence time on the vaginal surface. Prolonged surface contact is essential. Bioadhesives, which are classified as biocompatible polymers, may lengthen vaginal microbicide residence time, thus minimizing the need for frequent dosing, and their polymer scaffold can also help solubilize drugs. Developing a nontoxic bioadhesive that acts as a microbicide on its own and combining it with antiviral compounds will both lengthen residence time for the antiviral medication and add further protective properties. We propose to develop a combination microbicide using our patented, innovative, dual-element SR-2P bioadhesive polymer to deliver two therapeutics to the vaginal surface while simultaneously protecting this delicate tissue and creating a low-pH environment that aids in blocking human immunodeficiency virus (HIV)-1 infection. We will test this novel formulation both alone, for its inherent microbicidal properties; and formulate it with tenofovir and acyclovir, to demonstrate a safe and effective proof-of-principle product for the control of HIV-1 infections that, in combination, will be superior to current gel formulations. Preliminary studies performed by SRI researchers indicate that the SR-2P with tenofovir does not elicit any vaginal irritation. For the R21 phase, we will first optimize SR-2P with and without tenofovir and acyclovir to have strong bioadhesive and pH buffering properties, and to release drugs to the vaginal epithelium. In pilot batch manufacturing, we will produce sufficient drug product to test in subsequent safety and efficacy studies. Safety of SR-2P alone and in combination with the drugs will be investigated in a vaginal irritation model to demonstrate that the formulation is nontoxic and nonirritating. To develop SR-2P further in the R33 phase, we will test microbicide safety and efficacy of SR-2P with and without tenofovir and acyclovir in several models in vivo. Concurrently, we will perform accelerated stability studies on both forms. Using standard preclinical safety and toxicology methods, we will conduct vaginal pharmacokinetics/absorption; distribution, metabolism, excretion, and toxicity studies; and preclinical safety experiments to demonstrate that SR-2P is nonirritating and causes no tissue hypersensitivity. We anticipate that these studies will demonstrate that SR-2P is a safe and efficacious microbicide that can help reduce the further spread of HIV and HSV infections.